Hydroxyethylamino fluorenes



Patented Mar. '11, 1952 UNlTED STATES PATENT OFFICE HYDROXYETHYLAMINO FLUORENES James F. Kerwin and Glenn E. Ullyot,"-Philadelphia, Pa., assignors to Smith, Kline da French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Application August 25, 1949, Serial No. 112,397

6 Claims.

This invention relates to certain new'chemical compounds which are of value as intermediates in the preparationof other compounds I [I c l R z-N o-onon R! RI! in which Z is a member of the group consisting of phenylalkyl groups, the alkyl portion of which has not more than 4 carbon atoms and substituted phenylalkyl groups substituted in the phenyl ring, the alkyl portion of" which has not more than 4 carbon atoms and the substituents 'in the phenyl ring are selected from the group consisting of alkyl groups having not more than 4 carbon atoms, a methoxy group, a hydroxy group, chlorine, bromine and fluorine; R, R and R." are members of the group consisting of hydrogen and alkyl groups containing not more than 6 carbon atoms, the substituents for R, R and B" being selected so that the sum of the carbon atoms thereof does not exceed 6.

This invention also contemplates the salts of the above compounds formed with inorganic acids, as, for example, sulfamic, hydrochloric, hydrobromic, sulfuric, phosphoric, etc., and with organic acids, as, for example, tartaric, succinic, glycolic, camphorsulfonc, etc.

The compounds in accordance with this invention will be useful in the preparation of, for example, compounds having the following structure and which compounds will have physiological properties, such asadrenolytic Orsympathicolytic properties:

in which Z is a member of the group consisting of phenylalkyl groups, the alkyl portion of which has not more than 4 carbon atoms and substituted phenylalkyl groups substituted in the phenyl ring, the alkyl portion of which has not more than 4 carbon atomsand the substituents in the phenyl ring are selected from thegroup consistingof alkyl groupshaving not more than 4 carbon atomsya methoxy group,'ahydroxy group, chlorine, bromine and'fiuorine; RfR, and R" are members of the group-consisting of hydrogen' and alkyl" groups containing notmore than 6 carbon atomspthe substituents 'for R,-R.' and R being select'edsothat' the sum of the carbon atoms thereof does not exceed 6; and X is a member of the group consisting "of chlorine,

bromine and iodine; and salts thereof.

The above compounds form the'subject matter of a separate application for US; patent filed byus.

'In using the compounds of this invention as intermediates for the'preparation of the'above compounds, the hydroxylgroupwill be replaced with a halogen group, as bromine, chlorine; iodine, which will be effectedin any well known manner 'for replacing a 'hydroxyjgroup with a halogen, as by reactionwith athionyl halide, or with a halogen acid. The organic and inorganic salts of the above compounds Will be prepared in any well known manner, it being apparent that the above compounds will, reactwith' organic and inorganic acids generally in well known manner.

' I Generally speaking,zany' of the compounds in accordance with this invention as defined by the above structuralformulaewill be produced byinteracting 9-bromofluorene with an N-monosubstituted amino alcohol.

As more specifically illustrative of procedures generally applicable for making the compounds included within the structural formulae given above, 9-bromofiuorene and an amino alcohol are mixed and heated together until reaction is complete. The use of an excess of amino alcohol is desirable in order to remove hydrogen bromide, which is formed as a by-product of the reaction. If desired, a suitable solvent may be used, such as benzene, alcohol, or the like. Again, instead of using an excess of amino alcohol, the reaction may be carried out in the presence of an alkaline reagent, such as sodium bicarbonate,

a tertiary amine, such as dimethylaniline, diethylaniline, or the like.

On completion of the reaction, the product may be recovered by distillation or by effecting the formation of a hydrohalide salt and recrystallizing. The reaction will be made apparent by the following:

III

B it It In the above formula illustrative of the reactionfor the production of the compounds in accordance with this invention, Z, R, R. and R" are as indicated in connection with the above structural formula for the compounds according to this invention, it being obvious that for the preparation of compounds in accordance with this invention the particular amino alcohol for reaction with 9-bromofiuorene will be selected with consideration for the particular compound to be produced.

For the preparation of 9-(p-hydroxyethyl amino) fluorenes in accordance with this invention, a wide variety of amino alcohols may be used for reaction with 9-bromofluorene, many of which has been reported in the literature and others of which, given their structure as above, may be readily prepared by well known methods, see Cope and Hancock: J. Am. Chem. Soc., 64, 1503 (1942), Cope and Hancock: J. Am. Chem. Soc. 66, 1453 (1944) Hancock and Cope: J. Am. Chem. Soc. 66; 1738 (1944).

As alternative procedures for the preparation of B-(p-hydroxyethylamino) fiuorenes in accordance with this invention, an N-substituted 9- aminofluorene may be reacted with an alkylene oxide or with an alkylene halohydrin with heating, with or without the presence of a solvent,

the product being obtained from the reaction mixture, in the form of free base, by distillation oras a hydrohalide salt by recrystallization from a suitable solvent. The reaction according to this alternative method will be made apparent by the following:

R HO-CH-(l-Halogen The following compounds illustrate typical compounds of the various types having the above general structure and contemplated by this invention N- (9-fluorenyl) -N-benzylaminoethanol N- (9 fiuorenyl) -N- (fl-phenylisopropyl) -aminoethanol o -CH -CH-I ICHz-CHr-OH A) N(9 fiuorenyl) N (p methoxyphenylisopropyl) -aminoethanol 311 omoQom-on-rv-om-om-on I N (9 fluorenyl) N (p methoxybenzyD- 1-amino-2-propanol N-(Q-fluorenyl) N (p methylbenzyl) aminoethanol co l N-( 9 fiuorenyl) N (m-chlorobenzyl) aminoethanol aws- 49 butanol N -(9'-"fluorenyl) N -(2-chloro 6 -fiubrobenzyl) aminoethanol 1 N- (9-fiuorenyl) -N-phenethylaminoethano1 N- 9-fluorenyl) -N- (p -tert.-butylbenzyl) aminoethanol N-(Q-fluorenyl) N -(p-phenylbutyl) --amino-4- octanol N -(9 fluorenyll-N- (p-hydroxyphenylisopropy1) aminoethanol Example 1 For the preparation of N-(9-fluorenyD-N- benzylaminoethanol a solution of 49 grams of 9-bromofiuorene, 60.5 grams of benzylaminoethanol and 150 ml. of dry benzene are brought to boiling and refiuxed for two hours. Duringthis heating period, benzylaminoethanol hydrobromide crystallized from the reaction mixture. The

cooled mixture is filtered and the hydrobromide 16" salt washed with ether which is added to the "original filtrate.

lization from-a mixture of alcohol and acetone, it

. me1ts at 178.5179.5 C. e

'As illustrative of theuse of this product, for example, for thepreparation of N-(Q-fluorenyl) N benzyl 13 chlorethylamine hydrochloride, twenty-three grams of N-(Q-fluorenyl) N-benzylaminoethanol hydrochloride and 50 ml. of dry chloroform are cooled while'a solution of 8.5 g. of thionyl chloride in 50 ml. of chloroform is added. After heating at 45-50 C. for one and one-half hours, the solvent is evaporated in vacuo and the residue is recrystallized from-a mixture of chloroform and ether. The N-(Q-fiuo'renyD- N benzyl B-chlorethylamine hydrochloride so obtainedmelts at 184-186" C.

Example 2 By the procedure described'in Example 1, 54 g. of fi-phenylisopropylaminoethanol and 37 g. of 9-brom0fiuorene yields N-(Q-fiuOrenyD-N-(B- phenylisopropyl) aminoethanol. The hydrochloride melts at 186-187 C. By the action of thionyl chloride on this compound, as an intermediate, there is' obtained N-(Q-fiuorenyD-N- (p-phenylisopropyl) 13 chlorethylamine hydrochloride, Which melts at 187.5-188.5 0.

Example 3 For the preparation of N-(9-fluorenyl)-N- '(p-methoxyphenylisopropyl) aminoethanol, to prepare p-methoxyphenylisopropylaminoethanol, a solution of 82 g. of p-methoxyphenylacetone and 31 g. of ethanolamine in 100 ml. of alcohol is shaken under hydrogen pressure in the presence of platinum catalyst. After removal of the catalyst and alcohol the remainder is distilled to obtain the aminoethanol, B. P. 154157/2 mm.

A solution of 49 g. of Q-bromofiuorene and 83.6 g. of p-methoxyphenylisopropylaminoethanol in 150 ml. of benzene is refiuxed for two hours as in Example 1. The hydrobromide of the secondary amine separates and is removed by filtration. Addition of dry hydrogen chloride to the filtrate precipitates -N-(9-fiuorenyD-N-(pmethoxyphenylisopropyl) aminoethanol hydrochloride which can be purified by recrystallization from alcohol and ether The free base will be liberated by shaking thehydrochloride with an aqueous solution of a base suchas sodium hydroxide. 7

When the hydrochloride or free base is treated with thionyl chloride in-chloroform solution, the

corresponding B-chlorethylamine hydrochloride is formed. 7

Example 4 For the preparation of N-(Q-fiuOrenyD-N-(pmethoxybenzyl)-l-amino-2-propanol, a solution of one-half mole of p-methoxybenzaldehyde, onehalf mole'of 1-amino-2-propanol and ml. of alcohol is shaken under a hydrogen pressure of 3-4atmospheres in the presence of 0.5 g. of platinum oxide catalyst. Afterhydrogen absorption is substantially complete, the catalyst is filtered oif and N-(p-methoxybenzyl)-1-am'ino-2-propanol is recovered by distillation. f x.

For reaction of the amino alcohol with 9- bromofiuorene'the procedure of Example 1 is employed, heating onemole equivalent' of 9 .-bro"momethoxybenzyl)-1-amino-2-propanol in benzene solution. The product can be recovered as the hydrochloride as previously described or as the free base by distillation.

Reaction of the hydrochloride or free base as an intermediate with thionyl chloride in the manner described in the previous examples yields N (9 fluorenyl) N-(p-methoxybenzyl) -l-amino- 2-chloropropane hydrochloride.

. Example 5 For the preparation of N-(B-fluorenyl) -N-(pmethylbenzyl) aminoethanol, to synthesize this compound, p-methylbenzylaminoethanol is first prepared by reductive alkylation of p-methylbenzaldehyde and ethanolamine at 3 atmospheres hydrogen pressure and in the presence of platinum catalyst as previously described.

Forty-nine grams of B-bromofluorene and 66 g. of p-methylbenzylaminoethanol dissolved in 150 ml. of benzene are heated to reflex for two hours. The solution is separated from the secondary amine hydrobromide and the N-(Q-fluorenyl) -N- (p-methylbenzyl) aminoethanol is isolated as the hydrochloride salt or as the free base by distillation.

As an intermediate the compound will have utility in the preparation of N-(Q-fluorenyl) -N- (p-methylbenzyl) -p-chlorethylamine hydrochloride.

Example 6 For the preparation of N-(Q-fluorenyl) -N-(mchlorobenzyl) aminoethanol, m chlorobenzylaminoethanol is formed from m-chlorobenzaldehyde and ethanolamine by catalytic hydrogenation as described in previous examples.

Reaction of 9-bromofluorene and m-chlorobenzylaminoethanol in refluxing benzene solution as in Example 1 will produce the above amino alcohol which may be isolated as the free base by distillation, or as a salt.

Reaction of N- (Q-fluorenyl) -N-(n-chloroben zyl) aminoethanol as an intermediate with thionyl chloride in chloroform solution yields the corresponding fl-chloroethylamine hydrochloride.

Example 7 For the preparation of N-Q-fluorenyl) -N-(pbromobenzyl)-2-amino-1-butanol, a solution of equimolar quantities of p-bromo-benzaldehyde and Z-amino-l-butanol in alcohol is shaken under hydrogen pressure in the presence of platinum catalyst. The 2-(p-bromobenzylamino)-1- butanol which is formed is recovered by distillation.

Refiuxing a benzene solution of one mole equivalent of Q-bromofluorene and two equivalents of Z-(p-bromobenzylamino) -l-butanol as in Example 1 produces the tertiary amino alcohol.

As an intermediate the tertiary amino alcohol may be reacted with thionyl chloride to form N- (9 fluorenyl) N-(p-bromobenzyl) -2-amino-1- chlorobutane.

Example 8 For the preparation of N(9-fluorenyl)-N-(2- chloro-fi-fluorobenzyl) aminoethanol, as in the previous examples, catalytic reduction of 2- chloro-6-fluorobenzaldehyde with ethanolamine forms 2-chloro-fi-fluorobenzyl-aminoethanol. Reaction of this secondary amine with 9- bromofluorene in benzene solution as in Example 1 will give the desired product, N-(Q-fluorenyl) N-(2-chloro-6-fluorobenzyl) aminoethanol,

To illustratea use of this tertiary aminoalcohol, it may be reacted with thionyl chloride in chloroform solution to form N-(B-fluorenyl) N (2 chloro-6-fluorobeny1)-;8-chlorethy1amine hydrochloride.

Example 9 Example 10 For the preparation of N-(Q-fluorenyl) -N-'(ptert.-butylbenzyl) aminoethanol, hydrogenation of an alcohol solution of p-tert.-butylbenzaldehyde and ethanolamine produced p-tert.-butylbenzylaminoethanol.

The procedure of Example 1 is followed in alkylating p-tert.-butylbenzylaminoethanol with Q-bromofluorene to form the above compound.

The tertiary amino alcohol can be reacted with thionyl chloride to form N-(9-fluorenyl)-N- (ptert.-butylbenzy1) -B-chlorethylamine hydrochloride.

Example 11 Example 12 For the preparation of N-(Q-fluorenyD-N- (p-hydroxyphenylisopropyl) aminoethanol, N- (B-fluorenyl) N (p-methoxyphenylisopropyl) aminoethanol (Example 3) is heated with an excess of concentrated hydrobromic acid at C. for about 2 hours. The course of the reaction is followed by evolution of methyl bromide and when methyl bromide is no longer given on the reaction is complete. The hydrobromide of the product is then isolated by removing the hydrobromic acid in vacuo. The free base can be liberated by addition of bicarbonate solution to the hydrobromide salt.

In the foregoing examples aminoethanols and hydrochlorides thereof according to this invention are exemplified. However, it will be understood and readily appreciated by those skilled in the art that the foregoing examples will illustrate organic or inorganic salts generally and will serve, as will be obvious to anyone skilled in the art, as specific examples of those organic and inorganic salts heretofore mentioned specifically by the addition oi any of the acids heretofore specifically mentioned or any other desired organic or inorganic acid to the amino group in the several foregoing examples, respectively.

Procedure for the formation of any desired salt of the aminoethanols described will be obvious in all cases to those skilled in the art and in the light of the above disclosure, it being apparent that the several compounds will react with organic and inorganic acids generally under known procedure.

The compounds contemplated by this invention will be variously optically inactive or optically active and it will be understood that the optically inactive and optically active forms of the compounds contemplated by this invention are all included within the scope of this invention.

The various types of compounds having the structure embodying this invention as illustrated by the above specific examples will be readily prepared by the general methods of preparation described above as amplified by the description of preparation of the several specific examples. The

starting material for the preparation of any given compound within the structure contemplated by this invention will be found among known compounds, or, its structure being obvious with reference to any particular compound desired to be prepared, will be readily prepared by known methods.

This application is a continuation-in-part of application, Serial No. 37,494, filed July 7, 1948, now abandoned.

What is claimed is:

1. A product of the group consisting of the compound having the structure:

I II

in which Z is a member of the group consisting of phenylalkyl groups, the alkyl portion of which has not more than 4 carbon atoms and substituted phenylalkyl groups substituted in the phenyl ring, the alkyl portion of which has not more than 4 carbon atoms and the substituents in the phenyl ring are selected from the group consisting of lower alkyl groups, lower alkoxy groups, a hydroxy group, chlorine, bromine and fluorine; R, R and 3. A compound having the structure:

H3 4. A compound having the structure 5. A compound having the structure 6. A compound having the structure JAMES F. KERWIN. GLENN E. ULLYOT.

No references cited. 

1. A PRODUCT OF THE GROUP CONSISTING OF THE COMPOUND HAVING THE STRUCTURE: 